The type of tumor‐infiltrating macrophages may be decisive in tumor immunity, lymphangiogenesis and in the clinical outcome of cancer. Here, we elucidated the prognostic significance of lymphatic vessels, different types of macrophages and the balance between different macrophage types in colorectal cancer. We analyzed the impact of density, type and location of macrophages on the clinical behavior of 159 primary colorectal carcinomas using CD68 as a pan‐macrophage marker and CLEVER‐1/Stabilin‐1 as a marker for regulatory/suppressive macrophages. Podoplanin was used as a pan‐lymphatic vessel marker. A high number of CLEVER‐1/Stabilin‐1⁺ peritumoral macrophages positively correlated with survival (p = 0.04). However, in more advanced disease (Stage IV), the patients with a high number of peritumoral or intratumoral CLEVER‐1/Stabilin‐1⁺ macrophages had a shorter disease‐specific survival (p = 0.05, and p = 0.008, respectively). Moreover, a low number of suppressive intratumoral CLEVER‐1/Stabilin‐1⁺ macrophages among high numbers of CD68⁺ macrophages correlated with a low number of distant recurrences (p = 0.01) and to fewer disease relapses exclusively in the liver as well (p = 0.006). A high number of intratumoral lymphatics correlated with poor survival (p = 0.03). The results of this work suggest that the type of macrophages, number of lymphatic vessels and their location contribute to the clinical behavior of colorectal cancer in a disease stage‐specific manner.

Purpose: This study reviews our experience with deep neck space infections (DNIs) requiring surgical intervention, including cervical necrotizing fasciitis. The aim of the study was to identify predisposing and aggravating factors of the disease and recognize the possible factors that can lead to life-threatening complications and slow down the healing process. Methods: We compare the results to previous data from 1985 to 2005 to find possible alterations and changing trends. The characteristics of four lethal cases are described. This retrospective analysis includes patient data from 2004 to 2015 in tertiary referral hospital and in total, 277 patients were found. Results: Surgical drainage through a neck opening ± intraoral incision was made in 215 (77.6%) patients, an intraoral incision was only made in 62 patients (22.4%). ICU care was needed in 66 (23.8%) cases. Odontogenic etiology (44.8%) was the most common origin. The most common comorbidity was a psychiatric disorder and/or dementia and occurred in 55 (19.9%) patients. Patients with underlying illnesses were more likely to be admitted to the ICU (p = 0.020), required a longer ICU stay (p = 0.004) and repeated surgery (p = 0.009). Gas formation seemed to be predictive of a more severe course of infection. Early extraction of the odontogenic foci was related to a lower length of stay (LOS) (p = 0.039). Conclusion: The annual numbers have risen from 14 to 24 cases per year when compared to previous data. DNIs remain a cause of lethal complications; the mortality was 1.4% and overall complications occurred in 61 (22.0%) patients.

Purpose: Immunosuppressive leukocytes and vasculature are important host cell components regulating tumor progression. Clever-1/Stabilin-1, a multifunctional scavenger and adhesion receptor, is constitutively present on a subset of type II macrophages and lymphatic endothelium, but its functional role in cancer is unknown. Experimental Design: Here, we generated full Clever-1 knockout mice and cell-specific ones lacking Clever-1 either on macrophages or endothelium. We also used anti-Clever-1 antibody therapy to treat B16 melanoma and EL-4 lymphoma. Results: Clever-1–deficient mice had smaller primary and metastatic tumors than wild-type (WT) controls. Growth of primary tumors, but not of metastases, was attenuated also in mice lacking Clever-1 selectively in macrophages or in vascular endothelium. Anti-Clever-1 antibody treatment inhibited tumor progression in WT mice. Both genetically and therapeutically induced absence of functional Clever-1 led to diminished numbers of immunosuppressive leukocyte types in tumors. Functionally Clever-1 mediated binding of immunosuppressive leukocytes to the intratumoral blood vessels aberrantly expressing Clever-1, and tumor cell traffic via the lymphatics. The antibody therapy did not aggravate autoimmunity. Conclusion: This work identifies Clever-1 in type II macrophages and in tumor vasculature as a new immunosuppressive molecule in cancer. Our finding that Clever-1 supports binding of tumor-infiltrating lymphocytes to tumor vasculature increases our understanding of leukocyte immigration to tumors. The ability of anti-Clever-1 antibody treatment to attenuate tumor progression in WT mice in vivo is therapeutically relevant. Thus, Clever-1 may be an emerging new target for modulating immune evasion and lymphatic spread in cancer. Clin Cancer Res; 20(24); 6452–64. ©2014 AACR.

Clever‐1/Stabilin‐1 is a scavenger receptor present on lymphatic and sinusoidal endothelium as well as on a subset of type II macrophages. It is also induced on vasculature at sites of inflammation. However, its in vivo function has remained practically unknown and this work addresses those unknown aspects. We demonstrate using in vivo models that Clever‐1/Stabilin‐1 mediates migration of T and B lymphocytes to the draining lymph nodes in vivo and identify the adhesive epitope of the Clever‐1/Stabilin‐1 molecule responsible for the interaction between lymphocytes and lymphatic endothelium. Moreover, we demonstrate that Ab blocking of Clever‐1/Stabilin‐1 efficiently inhibits peritonitis in mice by decreasing the entrance of granulocytes by 50%, while migration of monocytes and lymphocytes into the inflamed peritoneum is prevented almost completely. Despite efficient anti‐inflammatory activity the Ab therapy does not dramatically dampen immune responses against the bacterial and foreign protein Ag tested and bacterial clearance. These results indicate that anti‐Clever‐1/Stabilin‐1 treatment can target two different arms of the vasculature – traffic via lymphatics and inflamed blood vessels.

Inflammation is an important feature of carcinogenesis. Tumor-associated macrophages (TAMs) can be associated with either poor or improved prognosis, depending on their properties and polarization. Current knowledge of the prognostic significance of TAMs in bladder cancer is limited and was investigated in this study. We analyzed 184 urothelial bladder cancer patients undergoing transurethral resection of a bladder tumor or radical cystectomy. CD68 (pan-macrophage marker), MAC387 (polarized towards type 1 macrophages), and CLEVER-1/Stabilin-1 (type 2 macrophages and lymphatic/blood vessels) were detected immunohistochemically. The median follow-up time was 6.0 years. High macrophage counts associated with a higher pT category and grade. Among patients undergoing transurethral resection, all studied markers apart from CLEVER-1/Stabilin-1 were associated with increased risk of progression and poorer disease-specific and overall survival in univariate analyses. High levels of two macrophage markers (CD68/MAC387^+/+ or CD68/CLEVER-1^+/+ groups) had an independent prognostic role after transurethral resection in multivariate analyses. In the cystectomy cohort, MAC387, alone and in combination with CD68, was associated with poorer survival in univariate analyses, but none of the markers were independent predictors of outcome in multivariate analyses. In conclusion, this study demonstrates that macrophage phenotypes provide significant independent prognostic information, particularly in bladder cancers undergoing transurethral resection.